The primary objective of this randomized, open-label, active-controlled, multi-center trial is to determine the efficacy of BIBW 2992 given as an add-on to chemotherapy in patients with NSCLC Stage IIIb or IV progressing after BIBW 2992 monotherapy compared to chemotherapy alone in this patient population. Patients on both treatment arms will receive best supportive care in addition to study treatment. Patients enrolled into the trial will be treated and followed until death or lost to follow-up. Additional information on the health-related quality of life (HRQOL) will be collected.

Progression Free Survival (PFS) Time as Determined by RECIST 1.1 for Part B. [ Time Frame: Every 8 weeks until the final follow-up visit in Part B, up to a total of 10 years. ] [ Designated as safety issue: No ]

PFS from the day of randomisation to the day of progression according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 for patients randomised to combination therapy with afatinib plus paclitaxel or to investigators choice of chemotherapy.

Secondary Outcome Measures:

Progression Free Survival (PFS) as Determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 for Part A [ Time Frame: tumour assessment was at screening (-28 days to screening) and every 6 weeks until the first follow-up visit in Part A, up to a total of 10 years. ] [ Designated as safety issue: No ]

Progression free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 for Part A. PFS from the day of randomisation to the day of progression according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 for patients treated with Afatinib monotherapy.

Overall Survival (OS) as Determined by the Time From Randomization to Death in Part B [ Time Frame: from the date of randomisation to the date of death, up to a total of 10 years. ] [ Designated as safety issue: No ]

Overall survival was calculated as the time from the date of randomisation to the date of death. Patients for whom there was no evidence of death at the time of the analysis were to be censored on the date that they were last known to have been alive.

Objective Response Rate According to RECIST 1.1 in Part B [ Time Frame: tumour assessment was every 8 weeks until the final follow-up visit in Part B, up to a total of 10 years. ] [ Designated as safety issue: No ]

Objective tumour response was defined as a best overall response of complete response (CR) or partial response (PR) as determined by RECIST 1.1 and as assessed by the Investigator. For patients enrolled in Part B, a Part B best overall response was to be based on all responses taken from the start of Part B treatment until the start of any new anticancer therapy or disease progression in Part B. The duration of objective response was defined as the time of first objective response to the time of progression or death, whichever occurred first (or date of censoring for PFS).

Objective Response According to RECIST 1.1 in Part A [ Time Frame: tumour assessment was at screening (-28 days to screening) and every 6 weeks until the first follow-up visit in Part A, up to a total of 10 years. ] [ Designated as safety issue: No ]

Objective tumour response was defined as a best overall response of CR or PR as determined by RECIST 1.1 and as assessed by the Investigator. For patients enrolled in Part A, this was to be based on all responses taken from the start of treatment until the start of any new anticancer therapy or disease progression. Objective response was analysed descriptively. The duration of objective response was defined as the time of first objective response to the time of progression or death, whichever occurred first (or date of censoring for PFS).

Patients should have received and failed at least one line of cytotoxic chemotherapy including a platinum-based regimen in patients eligible for platinum-based therapy and pemetrexed in pemetrexed eligible patients (unless pemetrexed is not considered a regulatory or clinical standard of care e.g. no label indication, no availability or no coverage by 3rd party payer(s)) for advanced or metastatic disease and have progressive disease following at least 12 weeks of treatment with erlotinib or gefitinib

Patients pretreated with taxane-based chemotherapy for advanced or metastatic disease must have experienced stable disease, partial or complete response as best response

Eastern Cooperative Oncology Group performance Score 0 or 1.

Patients with at least one tumor lesion that can accurately be measured by magnetic resonance imaging (MRI), or computed tomography (CT) in at least one dimension with longest diameter to be recorded as 10 mm but no less than double the slice thickness according to RESIST 1.1.

Male and female patients no less than 18 years of age.

Life expectancy of at least three (3) months.

Written informed consent that is consistent with ICH-GCP guidelines. Part B 1) Clinical benefit (disease stabilization or antitumor response) of 12 weeks duration in Part A of the trial determined on the second tumour assessment.

2.) Patients should have progressed in Part A according to RECIST 1.1 3.) New informed consent, including consent to biomarker sampling, must be signed before patients enter Part B of the trial

Active/symptomatic brain metastases including leptomeningeal disease. Patients with a history of treated brain metastasis must have a stable or normal brain MRT/CT scan at screening and be at least 4 weeks post-radiation or surgery for brain metastasis. Dexamethasone therapy will be allowed if administered as a stable dose for at least one month before randomization.

Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease, mal-absorption, or CTCAE Grade >2 diarrhea of any etiology at baseline

Patients who have any other life-threatening illness or organ system dysfunction, which in the opinion of the Investigator, would either compromise patient safety or interfere with the evaluation of the safety of the test drug

Other malignancies diagnosed within the past five (5) years (other than non-melanomatous skin cancer and in situ cervical cancer)

Radiotherapy within the past 2 weeks prior to treatment with the trial drug

Aspartate amino transferase (AST) or alanine amino transferase (ALT) at or greater than three times the upper limit of normal (if related to liver metastases at or greater than five times the upper limit of normal)

Serum creatinine at or greater 1.5 times the upper normal limit or calculated/measured creatinine clearance at or less than 45 mL/min

Women of child-bearing potential or men who are able to father a child unwilling to use a medically acceptable method of contraception during the trial

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01085136